This SBIR Phase II proposal is intended to further develop human ghrelin as a radiation medical countermeasure (MCM) to be approved by the FDA in the future. The risks of nuclear terrorism and nuclear power plant leaks still remain high, both of which can cause acute radiation injury on a large scale. Currently, there are limited drugs available to treat acute radiation syndrome (ARS). Human ghrelin is a 28-amino acid peptide hormone with broad effects on various body systems, including the endocrine, gastrointestinal (GI), cardiovascular, and immune systems. In our completed SBIR Phase I project, we have exposed rats and mice to total body irradiation (TBI) and demonstrated that subcutaneous administration of human ghrelin for 6 days, starting at 24 h post-TBI, significantly increased their survival rates and reduced their body weight loss. We further demonstrated, in the rat, that treatment with human ghrelin improved intestinal integrity and reduced gut apoptosis and permeability. Human ghrelin can be synthesized in large quantity for mass emergency needs. Moreover, human ghrelin has been tested in several clinical trials for other disease indications with an excellent safety profile. Based on our positive Phase I results, we hypothesize that human ghrelin can be developed as an effective post-exposure mitigator for acute radiation injury. In this proposal, we will use the mouse model of radiation injury to identiy the dose modification factor (DMF) of human ghrelin to treat GI-ARS and hematopoietic ARS (H- ARS). We will also examine human ghrelin's effect to attenuate hematopoietic and GI damages. In addition, we will conduct an exploratory study in non-human primates (NHP) to evaluate the effect of human ghrelin treatment on the GI and hematology response to radiation exposure. These proposed studies should provide crucial information on the efficacy of human ghrelin as a novel radiation MCM primarily targeting GI-ARS. Our ultimate goal is to obtain the FDA approval to use human ghrelin as a safe and effective treatment for people with acute radiation injury after a radiation emergency.